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| Ref Type | Journal Article | ||||||||||||
| PMID | (41686836) | ||||||||||||
| Authors | Huffman BM, Diossy M, Yurgelun MB, Horick N, Li YY, Crowdis J, Nguyen H, Parmar K, Kochupurakkal BS, Vonk L, Lam H, Ramsey K, Andrews E, Loeb SC, Culnane L, Biller LH, Bullock AJ, Enzinger A, Giannakis M, Jackson NA, Ng K, Nowak JA, Patel AK, Perez KJ, Rattani A, Rubinson DA, Schlechter BL, Singh H, Cai M, Raghavan S, Clark JW, Peters ML, Weipert CM, Wolpin BM, D'Andrea AD, Shapiro GI, Aguirre AJ, Szallasi Z, Cleary JM | ||||||||||||
| Title | A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2. | ||||||||||||
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| Abstract Text | PARP inhibition has demonstrated efficacy in patients with platinum-sensitive pancreatic cancer with germline BRCA1/2 pathogenic variants (PV). Whether PARP inhibitors might be effective in a broader population of patients with pancreatic cancer remains under investigation.This multicenter, open-label phase II trial (NCT03601923) enrolled patients with advanced pancreatic cancers who harbored germline or somatic BRCA1, BRCA2, PALB2, ATM, and/or CHEK2 PVs. Patients with prior progression on platinum-based therapy were excluded. Patients were treated with niraparib 200 or 300 mg once daily, with their initial dose determined by weight and platelet count. The primary endpoint was 6-month progression-free survival (PFS).Thirty-two patients [10 women (31%); median age: 67 years] were enrolled. Patients had a PV in at least one of the following genes: ATM (n = 14), BRCA2 (n = 10), PALB2 (n = 3), CHEK2 (n = 4), or BRCA1 (n = 2). The 6-month PFS was 25% [90% confidence interval (CI), 13%-41%] for the overall population, exceeding the preestablished threshold of 17%. The median PFS for the entire population was 2 months (95% CI, 1.4-3.8), and the objective response rate was 14% (95% CI, 4%-33%). All six patients with ≥6 months of PFS and evaluable tumor zygosity had biallelic inactivation of a DNA repair gene. Three patients with biallelic inactivation of ATM and no progression on prior chemotherapy received niraparib for more than 1 year.Niraparib demonstrated clinically meaningful benefit in a subset of patients. The prolonged PFS observed in patients with biallelic ATM loss warrants further investigation. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| ATM loss | pancreatic ductal adenocarcinoma | predicted - sensitive | Niraparib | Case Reports/Case Series | Actionable | In a Phase II trial, Zejula (niraparib) treatment in metastatic pancreatic ductal adenocarcinoma patients harboring mutations in ATM (n=14), BRCA1 (n=2), BRCA2 (n=10), CHEK2 (n=4), or PALB2 (n=3) resulted in a 6-month progression-free survival rate of 25%, objective response rate of 14% (4/32, 2 complete, 2 partial responses), and median overall survival of 10.2 mo in the overall cohort, and prolonged response greater than 1 year in 3 patients with biallelic ATM loss (PMID: 41686836; NCT03601923). | 41686836 |